The invention relates to the fields of rice fermentation and treatment of hyperlipidemia. More particularly, the invention relates to red rice fermentation products and methods, and use of the products to treat high cholesterol levels and other disorders.
The invention relates to compositions comprising red rice fermentation products, that can be used as dietary supplements and/or therapeutic medicaments. For example, the compositions can be used to lower serum cholesterol and triglycerides in mammals. Further, the invention relates to methods of treating cardiovascular disorders and other diseases using the red rice fermentation products. In addition, the invention relates to particular Monascus strains that yield fermentation products with the desired biological activities.
Red rice is known mostly for its use in food as a preservative and colorant, and its uses in the dye industry. Red rice (known in Chinese as Hung-ch""u or Hongqu) has also been known and used for hundreds of years in China in rice wine making and as a food preservative. In addition, red rice has been known as an ancient Chinese medicine or an ingredient in certain ancient Chinese prescriptions.
Red Rice was first used around the time of the Han Dynasty. Tao Gu, who lived in the age of Wudai after the Tang Dynasty, recorded xe2x80x9cRed Yeast Rice Cooked with Meat,xe2x80x9d in Qing Yi Lu. The method of making Red Rice was originally recorded in Tien Kyng K""ai Wu and Pen Ts""ao Kang Wu, A detailed description of the medical applications of red rice was provided in the ancient Chinese pharmacopoeia, Pen Ts""ao Kang Mu, which was published during the Ming dynasty (1368-1644). In Pen Ts""ao Kang Mu, Red Rice is described as mild, nonpoisonous, and useful for treating indigestion and diarrhea. Red Rice is also described as useful for improving blood circulation and promoting the health of the spleen and stomach. Furthermore, several xe2x80x9cprescriptionsxe2x80x9d using red rice for treating aliments, such as indigestion, diarrhea, and heart and abdominal pains, are also provided in this ancient work. In accordance with the Traditional Chinese Medicine Standard set forth in Pharmacopoeia of People""s Republic of China and the Traditional Chinese Medicine standard of Beijing, Nei Monggol, Shadog Provice, Jiangsu Province and Hunan province, etc., Red Rice is specified to be used as a traditional Chinese medicine. Furthermore, in the textbooks of Chinese universities and colleges such as Food Additives and Food Chemistry, Red Rice is considered as additives for food and beverages, and has been widely used in the food processing industry for the production of such items as fermented bean curd, beer, and meat.
In an abbreviated English translation of Pen Ts""ao Kang Mu published in 1911, red rice is described as useful for fermentation, and having medicinal value in the treatment of postpartum difficulties in women and dyspeptic conditions of children (Stuart, M. D., in xe2x80x9cChinese Materia Medicaxe2x80x94Vegetable Kingdom,xe2x80x9d page 233-234, republished in 1979 by Southern Materials Center, Inc., Taipei, Republic of China). Red rice, as described in Pen Ts""ao Kang Mu, was subsequently recognized to be the fungal species known as Monascus purpureus Went (Read, B. E., 1936, Chinese Medicinal Plants from the Pen Ts""ao Kang Mu, 3rd edition, published by Peking National History Bulletin; Klein, G., 1932, Handbuch der Pflanzenanalyse II, p. 1422-1423, Wien, Verlag von Julius Springer).
The manufacture of red rice is taught in another publication from the Ming dynasty, Tien Kung K""ai Wu by Sung Ying-Hsing, which was published in 1637 A.D. (see pages 291-294 in English translation of this ancient writing, xe2x80x9cTien Kung K""ai Wuxe2x80x94Chinese technology in the seventeenth century,xe2x80x9d translated by E-tu Zen Sun and Shiou-Chuan Sun. The Pennsylvania State University Press 1966). Red rice is described therein as useful for preserving the color and taste of fish or meat. The manufacturing process used red wine mash and cooked nonglutinous rice as starting materials. The method of making red rice by allowing the fungus to grow on the surface of cooked rice was also recorded by Voderman (1894. Analecta ob Cromatologisch Gebied. II. Geneesh. Fylschrift voor Ned. Indie, 35, No.5).
Modernly, red rice, the fermentation product of Monascus species, is still used in traditional Chinese medicine, wine making and food coloring in Asia and Asian communities in North America. The red and yellow pigments of Monascus purpureus, such as monascorubin and monascin, have been purified and extensively studied (Fielding et al., 1961, J Chem Soc, 4579-4589). The culture conditions and its effect on pigmentation of Monascus purpureus have also been studied (Broder et ad., 1980, J Food Sci, 45:567-469). Antibacterial activity, especially against Bacillus species, was also detected in Monascus purpureus extract (Wong, 1977, Plant Physiol, 60:578-581). The Red Rice of the traditional methods has been shown to be of little value and thus has gradually fallen out of use in medical applications. The traditional Red Rice has little effect of reducing blood lipids, and thus has never been used as a cholesterol lowering agent.
Lipids and lipoproteins play an essential role in transporting fat-derived metabolites between organs for absorption, metabolism, and distribution (Felig et al., 1975, N Eng J Med, 293:1078-1084). The susceptibility to dietary-induced elevations in blood lipids including cholesterol is extremely common. The interaction of genetic predisposition and a high fat, high caloric diet coupled with underactivity can lead to heart disease, hypertension, hypertriglyceridemia, and diabetes in a significant proportion of the United States population.
High serum cholesterol is a major risk factor for coronary artery disease. Cholesterol is a major component of atherosclerotic plaque. Other associated lipid abnormalities, including hypertriglyceridemia especially in the presence of lowered HDL cholesterol levels, have been recognized as contributing to the risk of cardiovascular disease. There is a reciprocal relationship between elevated triglyceride levels and lowered HDL levels.
The level of cholesterol in circulation results from the balance between production of apoB-100 particles and its removal from the circulation. Cholesterol is synthesized from acetyl-CoA via a series of more than 20 enzymatic reactions. This biosynthetic pathway is mainly regulated by the activity of HMG-CoA reductase (hydroxymethylglutaryl coenzyme A reductase), which catalyzes the reduction of HMG-CoA to mevalonate. Since the majority of cholesterol circulating is endogenously synthesized in the liver, and not derived from dietary cholesterol, inhibitors of enzymes that are involved in the biosynthesis of cholesterol have been explored as drugs for the treatment of hypercholesterolemia (Grundy, New Eng J Med (1988) 319:24-33).
One class of compounds inhibits cholesterol biosynthesis by competing with a natural substrate (HMG-CoA) for the key enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase. The first such hypocholesterolemic compound discovered was compactin, which was isolated from cultures of Penicillium citrinum by Akira Endo (Endo et al., J Antibiotics (1975) 29:1346-1348, see also U.S. Pat. Nos. 3,983,140, 4,049,495, and 4,137,322). The hypocholesterolemic activity of this compound was demonstrated in several animal species (Tsujita et al., Atherosclerosis (1979) 32:307-313). Thereafter, a hypocholesterolemic compound structurally related to compactin was independently discovered by Endo in fermentation products of Monascus ruber (the active compound was named monacolin K; Endo, J Antibiotics (1979) 32:852-854; Endo, J Antibiotics (1980) 33:334-336; see also German patents DE 3051175, 3051099 and 3006216; British patents GB 2046737 and 2055100), and by another group from cultures of Aspergillus terreus. The active compound was also named mevinolin, lovastatin or Mevacor(copyright); Tobert et al., J Clin Invest (1982) 69:913-919), and has been available in the United States since 1987 as a prescription drug. The efficacy and long term adverse effect of this active compound has been reviewed (Tobert, Am J Cardiol, 62:28J-34J). The isolated active compound, its derivatives and methods of production from Aspergillus have been reported; see U.S. Pat. Nos. 4,231,938, 4,342,767, 4,294,926, 4,319,039, 4,294,926, 4,294,846, and 4,420,491.
Although monacolin K or mevinolin has been successfully used to treat hypercholesterolemia, the compound has little or insignificant effect on the serum level of triglycerides. Other lipid regulating agents that have been used to treat hypertriglyceridemia, especially type IV and V hyperlipidemia, include nicotinic acid (e.g., niacin), and fibric acid derivatives (e.g., gemfibrozil and clofibrate). However, the uses of such agents are restricted because of their side effects, for example, high doses of niacin may cause gastric irritability, hyperuricemia hyperglycemia, pruritus, and gemfibrozil may lead to malignancy, gallbladder diseases, and abdominal pain. Moreover, the risk of myositis and rhabdomyolysis that can result in renal failure increases when monacolin K is combined with gemfibrozil, clofibrate or niacin. Such combinations are only used with careful supervision in special situations that warrant the risk (The Merck Manual, 1992, 16th edition, pages 1044-1046). High concentrations of serum triglycerides are known to be a risk factor for a variety of disease states and can lead to medical complications. Thus, there is a need for the development of a composition that accomplishes the reduction of the serum levels of both cholesterol as well as triglycerides. Regular exercise, proper nutrition, and weight reduction programs can prevent or reduce the incidence of common chronic diseases such as heart disease associated with elevations of blood lipids (Pi-Sunyer, Am J Clin Nutr (1991) 53:1595S-1603S). The role of diet in maintaining optimal health, and in slowing and reversing the progression of disease, has been the subject of much research and public attention. The development of an effective dietary supplement for use in the treatment of mixed hyperlipidemia, which could be used either with or without dietary changes, would be a significant benefit.
The invention relates to a product of the fermentation of at least one Monascus strain that can be used as a dietary supplement or as a therapeutic medicament to lower both serum cholesterol and triglyceride levels in humans. The invention is based, in part, on the surprising discovery that certain red rice products, i.e., the product of the fermentation of certain strains or mixtures of strains of Monascus, are effective at lowering not only the level of serum cholesterol but also the level of serum triglyceride in mammals, particularly humans. Since monacolin K and mevinolin are not known to be significantly effective in lowering serum triglyceride level, the beneficial effect of red rice products is likely to be related to other components in the fermentate.
In various embodiments of the invention, red rice can be used as a natural dietary supplement or a medicament to treat or prevent a variety of diseases, including but not limited to cardiovascular diseases, diabetes, fatty liver conditions, stroke, cerebral thrombosis, hypotension, hypertension and obesity, and to modulate the circulating levels of lipids, such as cholesterol and triglyceride. In addition, the present invention encompasses methods for treating or preventing these diseases in a human, which comprise administering to the human a therapeutically effective amount of a red rice fermentation product. The present invention also encompasses methods for improving or maintaining cardiovascular health in a human comprising administering to an effective amount of red rice fermentation product. The present invention further encompasses methods for reducing the serum cholesterol and serum triglyceride levels to normal levels in a human comprising administering to the human a therapeutically effective amount of a red rice fermentation product. Red rice can also be used to treat or prevent a variety of ailments or symptoms as related to diseases of the cardiovascular system.
According to the invention, red rice can be manufactured in various dosage forms and formulations. Also disclosed are methods for manufacturing red rice which are based on the traditional fermentation procedures.
The terms xe2x80x9cred rice fungixe2x80x9d or xe2x80x9cMonascusxe2x80x9d as used herein refer to the prefermented organism, while the terms xe2x80x9cred rice,xe2x80x9d xe2x80x9cred rice productxe2x80x9d, xe2x80x9cred rice extractxe2x80x9d and the like refer to a product that results from the fermentation of at least one Monascus. Further, these latter terms include traditional and improved red rice products as described below. More specifically, xe2x80x9cred rice productxe2x80x9d as used herein refers to the product of fermentation, e.g., the fermentate of one or a mixture of Monascus fungus. A xe2x80x9clovastatin-producingxe2x80x9d Monascus strain (such as strain 0272) is one which can be fermented to produce a product having a lovastatin content of at least 0.05%, preferably at least 2%.
The red rice product is the fermentation product of at least one of the following Monascus fungi set forth in the table below
Red rice is the fermentation product of one or a mixture of Monascus fungi, comprising chiefly Monascus purpureus Went, and in lesser proportions other Monascus species, e.g., Monascus ruber van Tieghem, Monascus Fuliginosus Sato, Monascus Pilosus Sato and Monascus albidus Sato. Red rice can also be the fermentation product of the following strains of Monascus fungi:
Monascus purpureus Went ATCC 30141, AS 3.562, AS 3.991, AS 3.4446 [ATCC 16365], AS 3.4642 [NRRL 2897], AS 3.4643 [NRRL 96], AS 3.4644, AS 3.4645, AS 3.4651; Monascus ruber van Tieghem AS 3.549, IFFI 05007, IFFI 05008, IFFI 05010, IPPI 05011; and Monascus anka IFFI 05038 (reference numbers provided in China Catalogue of Cultures, 1992, China Committee for Culture Collection of Microorganism, China Machine Press, Beijing 1992). The improved red rice of the invention comprises Monascus purpureus Went mutant strain M4027, 4028 and M4184.
The term xe2x80x9ctraditional red ricexe2x80x9d as used herein refers to a red rice product which is the result of fermentation using a mixture of Monascus fungi that has been used traditionally to manufacture red rice. xe2x80x9cTraditional red ricexe2x80x9d will generally contain less than about 0.005% lovastatin by weight. According to the invention, an xe2x80x9cimproved red ricexe2x80x9d is produced by fermentation using one or more natural or mutant strains of Monascus species, which yield a fermentate with improved biological or nutritional properties, e.g., higher hypocholesterolemic and hypotriglyceridemic activities than traditional red rice. The improved red rice of the invention comprises Monascus purpureus Went mutant strain CGMCC No. 0272. Several other strains can be used to achieve the objectives of the invention. Improved red rice is sometimes referred to as Xuezhikang herein.
Generally, the red rice products of the present invention are red-purple powders that have a slightly bitter but mild and pleasant taste. Similarly, the red rice products have a pleasant odor. The color and/or odor may vary with the fermentation process, the strains used and the processing steps. The red rice products of the invention contain at least 0.05% lovastatin, more preferably at least about 2.0% lovastatin by weight.
As used herein, the term xe2x80x9ceffective treatmentxe2x80x9d means the reduction of a particular symptom, or the significant change of a particular laboratory test toward the normal value. Preferably symptoms are relieved by at least 30-70% and a laboratory test is moved at least 10% toward the normal value; more preferably symptoms are reduced by 70% and/or a laboratory test is moved at least 20% toward the normal value; most preferably, a treatment is effective if the symptoms are reduced by 90%, and/or laboratory parameters are returned to the normal value.
The term xe2x80x9chypercholesterolemiaxe2x80x9d means the presence of elevated levels of cholesterol in the blood.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d or xe2x80x9ctherapeutic dosexe2x80x9d as used herein means the amount of a particular agent sufficient to provide a therapeutic benefit in the treatment or prevention of a disease, or in modulating the level of serum lipids and lipoproteins.
The term xe2x80x9cdietary supplementxe2x80x9d as used herein means an additional element that is added to the daily food intake of a mammal, usually a human.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages will be apparent from the following detailed description, and from the claims.
The invention relates to compositions comprising the product of the fermentation of at least one Monascus species. These compositions are useful for reducing the levels of both serum cholesterol and serum triglycerides in mammals, and in particular humans. In addition, the compositions are useful for modulating the levels of both serum cholesterol and triglycerides to maintain healthy levels despite intrinsic (e.g. aging) or extrinsic (e.g. stress) factors that affect serum cholesterol and triglyceride levels. The compositions and methods of the present invention are based, in part, on the discovery that the fermentate of Monascus species display hypocholesterolemic properties and also, unexpectedly, the ability to lower serum triglyceride levels. Since monacolin K is known not to be significantly effective in lowering serum triglyceride level, the beneficial effect of red rice products must be related to other components of the fermentate. The ability of red rice products to lower serum triglyceride level provides the art with a unique, natural alternative to the use of prescription hypocholesterolemic compounds.
According to the invention, traditional or improved red rice can be prepared by traditional fermentation procedures or by modification of the traditional procedures. According to the earliest reported method (Sung, 1637, Tien Kung K""ai Wu; pages 291-294, English translation by Sun et al., Pennsylvania State Press 1966), red rice can be prepared by the fermentation of washed and cooked nonglutinous rice using red wine mash, natural juice of Polygonum grass, and alum water. The rice is fermented in open air for 7 days on bamboo trays under very clean conditions. The rice changes its color from white to black, black to brown, brown to red and then red to yellow, which is then harvested as red rice. According to an alternative traditional method, nonglutinous rice can be fermented in a hole in the ground lined by bamboo mats, which is securely covered. Fermentation is allowed to take place underground for one year or more, up to four years.
With respect to the present invention, the traditional method has been improved by use of modem fermentation techniques and equipment to more precisely control temperature, pH, pressure and other fermentation parameters, which, inter alia, reduces the time of fermentation. The key feature of the improved red rice preparation is that it contains active ingredients that can prevent or treat hyperlipidemia and related cardiovascular diseases. The preparations can be made as follows:
For all of the media preparations rice or another grain is used as a carbon source. The carbon source can be rice (polished long-grain nonglutinous rice, polished round-grain nonglutinous rice, polished glutinous rice, red rice, and black rice), millet, barley, wheat, or corn. Additionally sugar and substances containing sugar can be used. Organic compounds such as glycerine and glyceride can also be used in the media preparations. For each 100 g of polished round-grained nonglutinous rice, 30-80 ml of culture medium are added. The culture media""s key feature is that the carbon source is selected from the group consisting of cereals, sugar, and organic compounds, the source of nitrogen is selected form the group consisting of beans (e.g. soya bean powder, pressed soybean cake), or peanut powder (or pressed peanut cake), peptone, rice extract powder, thick beef juice, silkworm chrysalis powder, or inorganic salts (e.g. NH4NO3, etc.), and a source of phosphorous can also be added, such as inorganic salts (e.g. KH2PO4, K2HPO4, etc). Other inorganic salts can also be added, such as MgSO4 or FeCl2. By way of an example, and not by limitation, media preparations of the invention are listed below:
2-7% glycerine (or malt or potato juice)
26% sugar
0-3% peptone
0.5-3% yeast extract powder
0-3% thick beef juice (optional)
2-4% defoamer (e.g. bean oil or peanut oil) water
0-5% Potato juice
0-6% sugar
0-1.5% yeast extract or peptone
30-80 ml of water per 100 g rice
2-4% potato juice
2-6% sugar
0.5-3% yeast extract powder (or peptone or thick beef juice) water.
Approximately 40-80 ml of the mixture is added to each 100 g of rice, the pH is maintained at 3-8, and it is sterilized in steam at 121xc2x0 C.
Generally, the pH is adjusted to 3.0-5.0, and the mixture is steam sterilized (121xc2x0 C.). The mixture is cooled to 40xc2x0 C. and the rice is inoculated with the a Monascus strain of the invention. For example, the Monascus purpureus Went strain CGMCC No. 0272 is added and cultured at 15-35xc2x0 C. for 9 days. Fermentation of the rice mixture is preferably carried out at a temperature of 15-35xc2x0 C., most preferably 20-28xc2x0 C., for over 4 days, most preferably 9 days or more, until the formation of Red Rice is noted. Any one of a number of methods of fermentation, well known to one of skill in the art, can be used. For example, an Erlenmeyer flask, tray, or ventilated fermentation bed can be used as fermentation facilities. At the end of the fermentation process, the fermentation broth is drained and discarded, while the solid residue is sterilized by heat (for example, by high pressure steam). For example, the fermentation product is sterilized at a temperature of 69-121xc2x0 C., and dried. This dried product can be ground. Standard mesh sizes for the production of capsules, tablets, powders and suspensions are well known in the art. By way of example, the improved red rice of the invention can be ground to 80 mesh under vacuum at a temperature of approximately 60-80xc2x0 C., and the powdered product recovered. This product can be used directly in the various compositions and formulations provided by the present invention. For example, it can be filled into capsules. Alternatively the 80 mesh ground product can further be ground to 200 mesh. The 200 mesh powder can then formulated into tablets using standard methodologies. Alternatively, liquid or syrup formulations of red rice can be made using conventional procedures.
Optionally, the dried crushed red rice powder can be further processed, e.g., extracted with organic solvents, such as but not limited to, alcohols (e.g. 75-90% ethanol) to remove starch and/or agar. After evaporation to dryness, the extract can be used in the various compositions and formulations as provided by the present invention. The extracted product can further be concentrated under a vacuum and evaporated (60-80xc2x0 C., 0.06-0.08 MPa) until dry. This provides an exceptionally useful supplement at very low cost.
According to the invention, an xe2x80x9cimproved red ricexe2x80x9d is produced by fermentation using one or more natural or mutant strains of Monascus species, which yield a fermentate with improved biological or nutritional properties, e.g., higher hypocholesterolemic and hypotriglyceridemic activities than traditional red rice. The improved red rice of the invention comprises Monascus purpureus Went mutant strain M4027, 4028 and M4184. Several other strains can be used to achieve the objectives of the invention (Chinese Microorganism Strain Index, 1992, China Microorganism Collection Committee), as listed in the Table above.
Lovastatin in red rice may be extracted using 10 ml of 75% EtOH at ambient temperature. The extract (2 ml) is treated with 1 ml 0.06 M NaOH in 75% EtOH for 30 min, then with 1 ml 0.06 N H3PO4 (in 75% EtOH, and the mixture applied to a C18 HPLC column (150xc3x974.60 mm), and developed with 0.02 N H3PO4 (in 70% MeOH) to quantify the amount of lovastatin present.
Red rice can be used as a natural dietary supplement or a pharmaceutical medicament to prevent illness (maintain health) or to treat or a variety of diseases, including but not limited to cardiovascular diseases, diabetes, stroke, hypertension and obesity, and to modulate the circulating levels of lipids and lipoproteins, such as cholesterol and triglycerides. Red rice can also be used to treat or prevent a variety of symptoms related to these above-mentioned diseases and associated with poor cardiovascular health due to aging and other intrinsic and extrinsic factors.
As used herein, examples of cardiovascular diseases may include but are not limited to myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis. The present invention includes the treatment or prevention of cerebrovascular disease such as stroke, memory loss due to stroke, and cerebral thrombosis.
The present invention also encompasses a composition comprising a therapeutically effective amount of a red rice product, for example 2-4 grams per day, useful in humans for the treatment or prevention of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, diabetes, fatty liver conditions, or obesity, or a combination thereof.
The present invention further encompasses a composition comprising a therapeutically effective amount of a red rice product, useful for the modulation of serum lipid and lipoprotein levels in a human in need of therapy to maintain the lipid and lipoprotein levels within a healthy normal range. In one embodiment of the invention, the composition is adapted for use in the treatment or prevention of hypertriglyceridemia. In a preferred embodiment, such a composition is used for reducing serum cholesterol and serum triglyceride levels in humans.
The present invention further encompasses a composition comprising a therapeutically effective amount of improved red rice product, useful for the treatment of any one of the following symptoms: shortness of breath; asthenic breathing; lethargy; dizziness; chronic headache; chest pain and tightness; heartache; loss of appetite; limb swelling; tightness and distention.
The improved red rice of the invention and preparations of the improved red rice contain statinoid compounds, i.e. hydroxy-acid Lovastatin and lactone Lovastatin. 
Without being bound by theory, the above-mentioned Monascus strains, when cultured under the appropriate fermentation conditions, have an increased content of the statinoid compounds. The increase in the statinoid compounds reduces serum cholesterol and serum triglycerides, while increasing high-density lipoprotein cholesterol simultaneously.
The red rice of the invention can be employed to treat hyperlipidemia and other related cardio-cerebrovascular diseases, such as atherosclerosis, coronary heart disease, myocardial infarction, diabetes, hypertension, and cerebral embolism, among others.
The present invention provides methods for treating a human afflicted by a variety of diseases, disorders, and symptoms. In addition to treatment of a human disease, the methods of the invention can also be used for preventive treatment in a person susceptible to such diseases, disorders or symptoms.
The invention encompasses methods of treatment of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension (hereditary and non-hereditary), hypotension, angina, stroke, diabetes, fatty liver conditions, or obesity, or a combination thereof in a human, comprising administering to the human a therapeutically effective amount of a red rice product, or compositions containing said product.
The invention also encompasses methods of preventing hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, angina, stroke, diabetes, fatty liver conditions such as fatty liver deposits, obesity or a combination thereof, which comprises administering an effective amount of a red rice product of the present invention. The method of the invention is preferably used to treat or prevent hypertriglyceridemia and associated diseases, such as diabetes, in humans.
As used herein, examples of cardiovascular diseases may include myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis, and cerebrovascular diseases or conditions, including stroke, cerebral thrombosis or memory loss due to stroke.
The present invention also provides methods for modulating serum lipid and lipoprotein levels in a human in need of lowering the lipid and lipoprotein levels to a healthy normal range, which comprise administering to the human a therapeutically effective amount of a red rice product, or compositions containing said product. In a preferred embodiment, the method of the invention is used to reduce serum cholesterol and serum triglyceride levels in a human. The methods of the invention are particularly useful for the treatment of geriatric patients and postmenopausal women.
The present invention further provides methods for treating a human afflicted by shortness of breath, asthenic breathing, lethargy, dizziness, chronic headache, loss of appetite, limb swelling, tightness and distention, and abdominal distention, or a combination thereof, which comprises administering to the human a therapeutically effective amount of a red rice product, or compositions containing said product.
The preventive or therapeutic dose of traditional red rice or improved red rice in the treatment or prevention of diseases and in the management of serum lipid and lipoprotein levels will vary with the condition to be treated and the severity of the condition to be treated. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range of red rice, for the conditions described herein, is from about 0.1 g to about 5 g administered in single or divided doses orally. For examples a preferred oral daily dose range should be from about 0.3 g to about 4 g, while most preferably an oral daily dose should be about 1.2 to about 2.5 g. For example, two capsules each containing 0.6 g of red rice may be taken orally twice a day to obtain the preferred dose. A course of treatment should be at least 4 weeks. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the nutritionist, dietitian, clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
It should be noted that the present invention encompasses new uses of traditional red rice, and novel red rice products and novel methods of using those products.
As mentioned above, the present invention encompasses compositions and methods of using traditional and novel or improved red rice products as dietary supplements. As such, the red rice products provide the individual with a means for maintaining normal or healthy levels of serum cholesterol and triglycerides despite intrinsic deterioration, e.g., from aging and extrinsic factors such as stress, lack or exercise and poor nutrition. The dietary supplements also provide means for preventing, or reducing the likelihood or experiencing, the diseases discussed above. Finally, the dietary supplements can be used to prevent weight gain or obesity. Finally, the dietary supplements containing red rice products are particularly useful for the elderly and postmenopausal women. The dietary supplements should be taken daily for at least four weeks and can be used permanently on a daily basis. A daily dose is from about 0.1 g to about 5.0 g; preferably about 1 to about 4 g; and most preferably about 1.2 to about 2.4 grams per day.
The pharmaceutical and dietary compositions of the present invention comprise a red rice product, or an extract thereof, as active ingredient, and may also contain a pharmaceutically acceptable carrier or excipient and, optionally, other ingredients.
Other ingredients that can be incorporated into the dietary or pharmaceutical compositions of the present invention may include, but are not limited to, vitamins, amino acids, metal salts and flavor enhancers. For oral administration, the compositions comprising red rice can be added directly to foods so that a therapeutically effective amount of red rice is ingested during normal meals. Any methods known to those skilled in the art may be used to add or incorporate red rice to natural or processed foods.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of a red rice product, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a nonaqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
The compositions of the present invention may additionally include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); binders or fillers (e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets or capsules can be coated by methods well known in the art.
Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), nonaqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations can also be made to resemble foods, containing buffer salts, flavoring, coloring and sweetening agents as appropriate.
Any dosage form may be employed for providing the patient with an effective dosage of the red rice product. Dosage forms include tablets, capsules, dispersions, suspensions, solutions, capsules and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers as described above are employed. In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means. However, the most preferred oral solid preparations are capsules.
For example, a tablet may be prepared by compression or molding, optionally, with one more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine red rice in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Most preferably, the composition is a capsule containing 0.3 g of red rice in powder form.
The invention is further defined by reference to the following examples describing in detail the human clinical trials conducted to study the efficacy and safety of red rice. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced which are within the scope of this invention.